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Intellectual disability

Gene: RNF135

Red List (low evidence)

RNF135 (ring finger protein 135)
EnsemblGeneIds (GRCh38): ENSG00000181481
EnsemblGeneIds (GRCh37): ENSG00000181481
OMIM: 611358, Gene2Phenotype
RNF135 is in 4 panels

3 reviews

Konstantinos Varvagiannis (Other)

Red List (low evidence)

Wright et al. (2019 - PMID: 30665703) based on the data from 379,768 UK Biobank participants conclude that disease association of RNF135 in developmental disorders is refuted.

The previously proposed phenotype consists of ID, macrocephaly and macrosomia as well as suggestive facial features. RNF135 haploinsufficiency was suggested based on the type of variants identified (mostly truncating) and the similar phenotype to 17q11 deletions spanning RNF135 but not other clinically relevant genes (such as NF1). The original publication by Douglas et al. (2007 - PMID: 17632510) seems to be the only relevant, at least for this mode of inheritance.

[A subsequent publication observed a significantly increased frequency of p.R114K (NM_032322.3:c.344G>A) in patients with autism (p=0.0019, OR:4.23 - CI:1.87-9.57). In particular, homozygosity for this variant was identified in 3 subjects with autism but was not observed in any of the 1812 control individuals included in the study. Tastet et al. - PMID: 26368817]

Based on 2 high-quality genotyped variants [NM_032322.3:c.727C>T - p.Q243X - MAF:0.00215% and chr17:29325809G>GC (GRCh37) - MAF:0.05265% - this variant seems however to affect the 3' UTR of some transcripts] and the documentation of clinically relevant traits in the UK biobank (eg. education years, fluid intelligence, BMI and height) no association was found to support pathogenicity of these variants.

Q243X was reported in one affected individual by Douglas et al. and has been submitted in ClinVar as pathogenic by OMIM (OMIM entry for this variant : https://www.omim.org/entry/611358?search=rnf135#0001 - ClinVar accession : SCV000021176).

Wright et al. note that the age of the original publication(s), the pLI score of 0 (in ExAC), and the lack of enrichment for de novo mutations in the DDD study suggest that RNF135 haploinsufficiency is not the cause of a severe developmental disorder.
Created: 30 Jan 2019, 3:09 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : Loss of function
Created: 27 Jul 2017, 8:15 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Louise Daugherty (Genomics England Curator)

Comment on list classification: Downgraded gene from Amber to Red due to external review highlighting new publication Wright et al. (2019 - PMID: 30665703) that refutes any evidence for developmental disorders (which includes ID)
Created: 29 Mar 2019, 9:27 a.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.
Created: 28 Jul 2017, 3:46 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Macrocephaly, macrosomia, facial dysmorphism syndrome, 614192
OMIM
611358
Clinvar variants
Variants in RNF135
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

29 Mar 2019, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: RNF135 were set to

29 Mar 2019, Gel status: 1

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: rnf135 has been classified as Red List (Low Evidence).

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to RNF135.

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

28 Jul 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

27 Jul 2017, Gel status: 0

Created

BRIDGE consortium (NIHRBR-RD)

RNF135 was created by BRIDGE

27 Jul 2017, Gel status: 0

Added New Source

BRIDGE consortium (NIHRBR-RD)

RNF135 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene